KR20100102688A - 17-HYDROXY-19-NOR-21-CARBOXYLIC ACID-STEROID γ-LACTONE DERIVATIVE, USE THEREOF, AND MEDICAMENT CONTAINING THE DERIVATIVE - Google Patents

Abstract

여기서, R⁴, R^6a, R^6b, R⁷, R¹⁵, R^16a, R^16b, R¹⁸ 및 Z는 청구항 제1항에 제시된 의미를 가진다. 본 발명은 또한 상기 유도체의, 경구 피임용, 및 폐경전, 폐경전후 및 폐경후 이상 치료용 약제의 제조를 위한 용도, 그리고 상기 유도체를 함유하는 약제에 관한 것이다. 본 발명에 따른 유도체는 프로게스테론 효과를 가지며, 바람직한 경우에는 항-광물 부신피질호르몬 효과 및 약간의 안드로겐에 대하여 중립성인 효과도 가진다.The present invention relates to a 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative having the formula (I) and solvates, hydrates, stereoisomers and salts thereof,
<Formula I>

Wherein R ⁴ , R ^6a , R ^6b , R ⁷ , R ¹⁵ , R ^16a , R ^16b , R ¹⁸ and Z have the meaning given in claim 1. The present invention also relates to the use of the derivatives for oral contraception and for the preparation of medicaments for premenopausal, premenopausal and postmenopausal disorders, and for medicaments containing the derivatives. The derivatives according to the invention have a progesterone effect and, if desired, also an anti-mineral corticosteroid effect and a neutral and neutral effect on some androgens.

Description

17-Hydroxy-13-nor-21-carboxylic acid-steroid γ-lactone derivatives, uses thereof, and pharmaceuticals containing the derivatives , USE THEREOF, AND MEDICAMENT CONTAINING THE DERIVATIVE}

The present invention provides certain 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivatives, their use, and for example, premenopausal, premenopausal and postmenopausal, and premenstrual complaints. It relates to a pharmaceutical product containing the derivative having a progestational action for the treatment of.

Compounds with progesterone, anti-mineral corticosteroids, anti-androgens or anti-estrogen activity based on steroid structure are for example derived from 19-nor-androst-4-en-3-one or derivatives thereof. Known (numbering of steroid structures is given, for example, in Fresenius / Gorlitzer 3rd Ed. 1991 "Organic-Chemical Nomenclature" p. 60 ff.).

For example, WO 2006072467 A1 has a progesterone action and has been used, for example, in compounds 6β, 7β; 15β, 16β-dimethylene-3-oxo-17-, which have been used in oral contraceptives and pharmaceuticals for the treatment of postmenopausal complaints. Pregne-4-ene-21,17β-carbolactone (drospirenone) is disclosed. However, due to its relatively low affinity for the progestogen receptor, and its relatively high ovulation-inhibiting dose, drospirenone is contained in the contraceptive at 3 mg, which is a relatively high daily dose. Drospyrenone is also characterized by having aldosterone-antagonism (anti-mineral adrenal cortex hormone) and anti-androgen action in addition to progesterone action. These two properties make drospirenone very similar to natural progestogen, progesterone, which, in its pharmaceutical profile, is not orally bioavailable, unlike drospirenone. In order to lower the dose to be administered, WO 2006072467 A1 additionally discloses 18-methyl-19-nor-17-pregin-4-ene-21,17-carbolactone having higher progesterone potency than drospirenone and A pharmaceutical preparation containing the same is proposed.

US-A 3,705,179 also discloses steroids that exhibit anti-androgen activity, for example, and which are suitable for the treatment of diseases associated with androgen.

US Pat. No. 2,918,463 also discloses 17-carboxyalkylated 17-hydroxy-19-, including 17α- (2-carboxyvinyl) -17β-hydroxy-19-nor-androst-4-en-3-one lactone. Noroandrosten-3-one is disclosed. The compounds are said to block the action of deoxycorticosterone acetate on sodium and potassium concentrations in the urine and at the same time have a salt-binding action at higher concentrations. The compounds are also mentioned to be effective against hypertension.

It is an object of the present invention to prepare soluble compounds that bind strongly to progestogen receptors. In addition, the compound should preferably also have anti-mineral corticosteroid action and be neutral for some androgen action with respect to androgen receptors. Another essential object of the present invention consists in achieving a balanced action profile with respect to progesterone action versus antimineral corticosteroid action, such that the ratio of progesterone action to antimineral corticosteroid action is less than that of drospirenone.

This object is the 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to claim 1 of the present invention, the use of the derivative according to claim 17 of the present invention, and the present A pharmaceutical product containing at least one derivative according to claim 19 of the invention. Advantageous embodiments of the invention are set out in the dependent claims.

Accordingly, the present invention relates to a 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative having the formula (I) and solvates, hydrates, stereoisomers and salts thereof,

<Formula I>

here

Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'and NNHSO ₂ R', wherein R 'is hydrogen, C ₁ -C ₁₀ -alkyl, aryl or C ₇ -C ₂₀ -aralkyl,

R ⁴ is selected from the group containing hydrogen and halogen,

Also

R ^6a , R ^6b are each independently of each other selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl and C ₂ -C ₁₀ -alkynyl, or together methylene or To form 1,2-ethanediyl,

R ⁷ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₁₀ -alkenyl and C ₂ -C ₁₀ -alkynyl, or

or

R ^6a , R ⁷ together form an oxygen atom or methylene, or are omitted with the formation of a double bond between C ⁶ and C ⁷ ,

R ^6b is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl and C ₂ -C ₁₀ -alkynyl,

Also

R ¹⁵ is hydrogen,

R ^16a , R ^16b are each independently selected from each other from the group comprising hydrogen and C ₁ -C ₁₀ -alkyl, or together form methylene or 1,2-ethanediyl,

or

R ¹⁵ and R ^16a are omitted together to form an oxygen atom or to form a double bond between C ¹⁵ and C ¹⁶ ,

R ^16b is hydrogen or C ₁ -C ₁₀ -alkyl,

R ¹⁸ is hydrogen or C ₁ -C ₃ -alkyl,

Provided that 17α- (2-carboxyvinyl) -17β-hydroxy-19-nor-andro-4-en-3-one γ-lactone (17β-hydroxy-19-nor-17α-pregna-4, 20 (Z) -dien-3-one-21-carboxylic acid γ-lactone) is excluded.

The numbering of the derivative carbon skeletons according to the invention having the general formula (I) follows the steroid structure numbering in the general manner, as described, for example, in the cited Fresenius. With respect to R ⁴ , R ⁶ , R ⁷ , R ¹⁵ , R ¹⁶ and R ¹⁸ , the numbering of the residues mentioned in the claims similarly corresponds to their binding position on the derivative carbon skeleton. For example, residue R ⁴ binds to the C ⁴ -position of the derivative according to the invention.

For the groups defined in Z, the groups NOR 'and NNHSO ₂ R' are bonded to the carbon skeleton of the derivative by double bonds through N depending on = NOR 'or = NNH-SO ₂ R', respectively. OR 'at NOR ′ and NHSO ₂ R ′ at NNHSO ₂ R ′ may be at the same- or opposite-position.

Alkyl at R ¹⁹ , R ²⁰ , R ^21a , R ^21b and R ²² of R ′, R ^6a , R ^6b , R ⁷ , R ^16a and R ^16b , and further general formulas which will be presented later is 1-10 Linear or branched alkyl groups having carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. Alkyl in R ¹⁸ means especially methyl, ethyl, propyl or isopropyl. The alkyl groups R ′, R ^6a , R ^6b , R ⁷ , R ^16a , R ^16b and R ¹⁸ may also be perfluorinated or 1-5 halogen atoms, hydroxyl groups, C ₁ -C _4- It may be substituted by an alkoxy group, a C ₆ -C ₁₂ -aryl group, which in turn may be substituted by 1-3 halogen atoms. Thus, in particular, alkyl is hydroxymethylene (HO-CH ₂ ), hydroxyethylene (HO-C ₂ H ₄ ), hydroxypropylene (HO-C ₃ H ₆ ) and hydroxybutylene (HO-C ₄ H ₈ ) And isomers thereof.

Alkenyl at R ^6a , R ^6b and R ⁷ is a linear or branched alkenyl group having 2-10 carbon atoms, for example vinyl, propenyl, butenyl, pentenyl, isobutenyl, isopentenyl Means.

Alkynyl at R ^6a , R ^6b and R ⁷ is a linear or branched alkynyl group having 2-10 carbon atoms, for example ethynyl, propynyl, butynyl, pentynyl, isobutynyl, iso Means fentinyl.

The alkenyl and alkynyl groups R ^6a , R ^6b and R ⁷ represent 1-5 halogen atoms, hydroxyl groups, C ₁ -C ₃ -alkoxy groups, C ₆ -C ₁₂ -aryl groups (these are again 1-3 May be substituted with 2 halogen atoms).

Cycloalkyl in R ^{7 means} a cycloalkyl group having 3-6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Said cycloalkyl group R ⁷ is halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, NH ₂ , NO ₂ , N ₃ , CN, C ₁ -C ₁₀ -alkyl, C ₁ -C ₁₀ -acyl , May be substituted by a C ₁ -C ₁₀ -acyloxy group.

Aryl at R 'is a substituted and unsubstituted carbocyclic or heterocyclic moiety having one or more heteroatoms, for example halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, NH ₂ , NO Phenyl, naphthyl, furyl, thie, which may be substituted singly or multiplely by ₂ , N ₃ , CN, C ₁ -C ₁₀ -alkyl, C ₁ -C ₁₀ -acyl, C ₁ -C ₁₀ -acyloxy groups Niyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl. Unless aryl is otherwise stated as a substituent on alkyl, alkenyl or alkynyl, it is particularly relevant for aryl groups having 6-12 ring carbon atoms.

Aralkyl at R 'and R ⁷ contains up to 14 carbon atoms, preferably 6 to 10 carbon atoms in the ring, and 1 to 8, preferably 1 to 4 carbon atoms in the alkyl chain. It means an aralkyl group which may contain. As the aralkyl moiety, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl may be considered. The ring is halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, NO ₂ , N ₃ , CN, C ₁ -C ₂₀ -alkyl, C ₁ -C ₂₀ -acyl, C ₁ -C _20- It may be substituted alone or multiplely by an acyloxy group.

When alkoxy (O-alkyl) is mentioned as a substituent on alkyl, it refers to an alkoxy group having 1-4 carbon atoms, and when alkoxy is mentioned as a substituent on alkenyl and alkynyl, it is 1-3 carbon atoms Refers to an alkoxy group having Alkoxy may especially be methoxy, ethoxy and propoxy.

When acyl (CO-alkyl) is mentioned as a substituent on cycloalkyl and aryl, it refers to an acyl group having 1-10 carbon atoms, and when acyl is referred to as a substituent on aralkyl, it is 1-20 carbon atoms It refers to an acyl group having. Acyl may in particular be formyl, acetyl, propionyl and butyryl.

When acyloxy (O-CO-alkyl) is mentioned as a substituent on cycloalkyl and aryl, it refers to an acyloxy group having 1-10 carbon atoms, and when acyloxy is mentioned as a substituent on aralkyl, it is 1 It refers to an acyloxy group having -20 carbon atoms. Acyloxy may especially be formyloxy, acetyloxy, propionyloxy and butyryloxy.

Halogen means fluorine, chlorine or bromine.

In a preferred embodiment of the invention, Z is selected from the group comprising oxygen, NOR 'and NNHSO ₂ R'.

In another preferred embodiment of the invention, Z represents oxygen.

In another preferred embodiment of the invention, R ⁴ is hydrogen or chlorine.

In another preferred embodiment of the invention, R ^6a , R ^6b together form 1,2-ethanediyl, or each is hydrogen.

In another preferred embodiment of the invention, R ⁷ is selected from the group comprising hydrogen, methyl, ethyl and vinyl.

In another preferred embodiment of the invention, R ^6a , R ⁷ together form methylene.

In another preferred embodiment of the invention, R ^6a and R ⁷ are omitted, forming a double bond between C ⁶ and C ⁷ .

In another preferred embodiment of the invention, R ¹⁵ is hydrogen.

In another preferred embodiment of the invention, R ¹⁵ , R ^16a are omitted, forming a double bond between C ¹⁵ and C ¹⁶ , or R ¹⁵ , R ^16a together form an oxygen atom.

In another preferred embodiment of the invention, R ^16a is hydrogen and R ^16b is methyl.

In another preferred embodiment of the invention, R ^16a and R ^16b are hydrogen.

In another preferred embodiment of the invention, R ^16a and R ^16b together form methylene or 1,2-ethanediyl.

In another preferred embodiment of the invention, R ¹⁸ is hydrogen or methyl.

Compounds having Formula I

Z is oxygen, the group NOR ', where R' is hydrogen, C ₁ -C ₆ -alkyl, aryl or C ₇ -C ₁₂ -aralkyl,

R ⁴ is hydrogen or halogen,

R ^6a , R ^6b are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, or together form methylene or 1,2-ethanediyl and ,

R ⁷ is hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, or

or

R ^6a , R ⁷ are omitted with the formation of a double bond between C ⁶ and C ⁷ , or together form methylene,

R ^6b is selected from the group comprising hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl,

Also

R ¹⁵ is hydrogen,

R ^16a , R ^16b are independently of each other hydrogen or C ₁ -C ₆ -alkyl, or together form methylene or 1,2-ethanediyl,

or

R ¹⁵ and R ^16a are omitted as a double bond is formed between C ¹⁵ and C ¹⁶ ,

R ^16b is hydrogen or C ₁ -C ₆ -alkyl,

R ¹⁸ is preferably hydrogen, methyl or ethyl.

Compound of Formula (I)

Z is oxygen or a group NOR ', R' is hydrogen or C ₁ -C ₃ -alkyl,

R ⁴ is hydrogen, chlorine or bromine,

R ^6a , R ^6b are independently of each other hydrogen, C ₁ -C ₃ -alkyl or C ₂ -C ₄ -alkenyl, or together form methylene or 1,2-ethanediyl,

R ⁷ is hydrogen, C ₁ -C ₄ -alkyl, C ₃ -C ₄ -cycloalkyl or C ₂ -C ₄ -alkenyl, or

or

R ^6a , R ⁷ are omitted with the formation of a double bond between C ⁶ and C ⁷ , or together form methylene,

R ^6b is hydrogen, C ₁ -C ₃ -alkyl or C ₂ -C ₄ -alkenyl,

Also

R ¹⁵ is hydrogen,

R ^16a , R ^16b are hydrogen or together form methylene or 1,2-ethanediyl, or

or

R ¹⁵ and R ^16a are omitted as a double bond is formed between C ¹⁵ and C ¹⁶ ,

R ^16b is hydrogen,

It is particularly preferred that R ¹⁸ is hydrogen or methyl.

All possible stereoisomers of the compounds having the general formula (I) and isomeric mixtures including racemates are expressly included, and the position of the unsaturated γ-lactone ring in the derivative according to the invention is also in two isomeric forms. May occur. Each of the substituents mentioned on the steroid basic structure may be in both the α- and β-positions. In addition, the substituents on the steroid base structure containing a double bond and having one or more substituents where the double bond for each carbon atom is not hydrogen may be arranged in both E- and Z-. Groups bonded to two adjacent carbon atoms in the structure, for example oxygen atoms, methylene or 1,2-ethanediyl, are bonded to either the α, α-position or β, β-position.

All crystal modifications of the compound having general formula (I) are also explicitly included.

Derivatives according to the invention in the form of solvates, in particular hydrates are also explicitly included, whereby the compounds according to the invention may contain polar solvents, in particular water, as structural elements of the compound crystal lattice according to the invention. The polar solvent, in particular water, may be present in stoichiometric ratios or even in non-stoichiometric ratios. Stoichiometric solvates and hydrates are also referred to as solvates or hydrates such as hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- and the like.

In the presence of acid functional groups, physiologically compatible salts of organic and inorganic bases are suitable as salts, examples of which are readily soluble alkali-metal and alkaline earth salts, and N-methyl-glucamine, D- Methyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, cerinol, tris-hydroxy-methyl-aminomethane, aminopropanediol, Sovak- Base, a salt of 1-amino-2,3,4-butanetriol. Where basic functional groups are present, physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and the like.

It has been found that the compounds or derivatives according to the invention have good progesterone action. In addition, some interesting compounds according to the present invention can confer antagonism by interacting with the mineral corticosteroid receptors. In addition, the compounds according to the invention are neutral to some androgen action with respect to the androgen receptor. Another property of major compounds is that the binding of the compounds to the progesterone receptor and the mineral corticosteroid receptor is balanced relative to each other, ie the ability to bind its progesterone receptor versus the mineral corticosteroid receptor The ratio of is less than that in the case of drospirenone. Thus, the antimineral corticosteroid action of the compound at a given progesterone action is less than that of using drospirenone. Thus, given a dose of a compound according to the invention based on its progesterone action, the antiminergic corticosteroid action of the compound at that dose is less than that with drospirenone.

In the present invention, the compounds listed below are particularly preferred:

Based on progesterone potency, the novel compounds having the general formula (I) can be used either alone or in combination with estrogens in contraceptive medicinal products.

Thus, the derivatives according to the invention are particularly suitable for the preparation of pharmaceutical products for oral contraception and for the treatment of premenopausal, premenopausal and postmenopausal complaints, including use in pharmaceutical preparations for hormone replacement therapy (HRT). Do.

Because of the preferred action profile, the derivatives according to the invention are also very particularly suitable for the treatment of premenstrual complaints such as headaches, depression, water retention and breast pain.

The use of the derivatives according to the invention is particularly preferred for the preparation of progesterone, and preferably also pharmaceutical products having anti-minergic corticosteroid action, and neutral to some androgen action.

Treatment with the derivatives according to the invention is preferably applied to humans, but can also be carried out on relevant mammalian species, for example dogs and cats.

In the use of the derivatives according to the invention as medicinal products, it is combined with one or more suitable pharmaceutically harmless additives, for example carriers. The additive is for example suitable for parenteral, preferably oral application. Related materials include pharmaceutically suitable organic or inorganic inert additives such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. The pharmaceutical product may be, for example, in solid form as a tablet, coated tablet, suppository, capsule, or in liquid form, for example as a solution, suspension or emulsion. Optionally, it also contains excipients such as preservatives, stabilizers, wetting or emulsifying agents, salts or buffers to alter the osmotic pressure. For parenteral applications, oil solutions are particularly suitable, for example solutions in sesame oil, castor oil and cottonseed oil. To increase the solubility, solubilizers such as benzyl benzoate or benzyl alcohol can be added. It is also possible to apply the derivative according to the invention in a transdermal system and to apply it transdermally. For oral application, in particular tablets, coated tablets, capsules, pills, suspensions or solutions can be considered.

Another example of a route of administration is intravaginal or intrauterine administration. This is possible using physiologically acceptable solutions, such as, for example, aqueous or oil solutions with or without suitable solubilizers, dispersants or emulsifiers. Examples of suitable oils are peanut oil, cottonseed oil, castor oil or sesame oil. Choice is not limited to this.

For intravaginal or intrauterine administration, an intravaginal system (such as vaginal rings, VRS) or intrauterine system (IUS) that releases the active substance of the present invention from a container for a long period of time (such as 1, 2, 3, 4 or 5 years). It is possible to use special systems such as

A representative example of an intrauterine system that may be mentioned is MIRENA®. This is a T-shaped levonorgestrel-releasing intrauterine system from Bayer Schering Pharma AG.

Administration is also possible via an implantable reservoir system consisting of an inert carrier material such as, for example, a biodegradable polymer or a synthetic silicone polymer. Such reservoir systems release the active ingredient in a controlled manner over a long period of time (such as 3 months to 3 years) and are implanted subcutaneously.

The dosage of the derivatives according to the invention in the contraceptive preparation should be 0.01 to 10 mg per day. The daily dose in the treatment of premenstrual complaints is around 0.1 to 20 mg. The progesterone derivatives according to the invention in the contraceptive preparation and the medicinal product for the treatment of premenstrual complaints are preferably administered orally. The daily dose is preferably administered as a single dose. The above mentioned dosages relate to oral dosage forms.

In the use of reservoir formulations, suitable dosages equivalent to the oral dosages mentioned above are used for long periods of time by continually being released daily from the reservoir system described above.

Depot preparations, such as IUS, release the compound of Formula 1 in an amount of 0.005 to 10 mg per day.

Progesterone and estrogen active ingredients are preferably applied together orally in contraceptive preparations. The daily dose is preferably administered as a single dose.

As estrogens, natural estrogens, including synthetic estrogens, preferably ethynylestradiol as well as mestranol, and phytoestrogens, can be considered.

Estrogen is administered in an amount per day corresponding to the pharmaceutical activity of 0.01 to 0.04 mg of ethynylestradiol. The amount relates to an oral dosage form. If other routes of administration are chosen, appropriate dosages equivalent to the oral dosages mentioned above should be used.

Examples of estrogens in pharmaceutical products for premenopausal, premenopausal and postmenopausal complaints, and hormone replacement therapy include natural estrogens, especially estradiol, as well as esters of estradiol, such as estradiol valerate, and also conjugated estrogens. (conjugated estrogen) (CEE = conjugated horse estrogen) is mainly used.

The progesterone, antiminergic corticosteroid, and androgen or antiandrogen action of the compounds according to the invention were investigated by the following methods:

1. Progesterone Receptor Binding Test:

Cytoplasmic fluid from progesterone receptor-expressing insect cells (Hi5) was used to measure competitive binding to progesterone receptors by the ability to substitute ³ H-progesterone as a reference material from the receptor. If the compound has affinity corresponding to progesterone, this corresponds to the competition coefficient (CF) 1. CF values above 1 are characterized by lower affinity for progesterone receptors, and CF values below 1 are characterized by higher affinity.

2. Mineral corticosteroid receptor binding test:

The test was performed as in 1, using the following modifications: cytoplasm from mineral adrenal cortex hormone receptor-expressing insect cells (Hi5) was used and the reference material was ³ H-aldosterone.

3. Androgen Receptor Binding Test:

The test was carried out as in 1, using the following modifications: cytoplasm from androgen receptor-expressing insect cells (Hi5) was used and the reference material was ³ H-testosterone.

The results of the binding tests and the ratio of competition coefficients CF (PR) and CR (MR) are shown in Table 1, which also shows the receptor binding value of drospirenone as reference material A for comparison.

4. Measurement of progesterone action by cross activation test:

The culture medium used for the culturing of the cells used in the assay was 10% FCS (Biochrom, S0115, Batch # 615B), 4 mM mM L-glutamine, 1% penicillin / streptomycin, 1 mg / ml G418 and DMEM with 0.5 μg / ml puromycin (Dulbecco's Modified Eagle Medium: 4500 μg / ml glucose; PAA, # E15-009).

Well reporter cell lines (CHO K1 cells stably nucleic acid transfected using reporter constructs containing fusion proteins from the PR-ligand-binding domain and Gal4-cross-activation domain, and luciferase under control of the Gal4-responsive promoter) Inoculated into white opaque tissue culture plates (PerkinElmer, # P12-106-017) each having 96 wells at a density of 4 × 10 ⁴ cells per cell, and treated with 3% DCC-FCS (activated carbon and serum Serum) from which the interference components contained in were removed). After 8 hours test compounds were added and cells were incubated for 16 hours using the test compounds. The test was performed in three replicates. After incubation, the medium containing the effector was removed and replaced with lysis buffer. After adding luciferase assay substrate (Promega, # E1501), the 96-well plate was then placed in a microplate luminometer (Pherastar, BMG Labtech) and luminescence Was measured. IC ₅₀ values were evaluated using software for dose-effect relationship calculation. Table 2 shows the test results and the corresponding results in drospirenone as reference material A for comparison.

5. Determination of anti-mineral corticosteroid activity by cross-activation test:

The anti-mineral corticosteroid activity of the test substance was measured as in the cross-activation test described above.

The following modifications were used: in this case a reporter cell line (MDCK cell) expressing a human mineral corticosteroid receptor and temporarily containing a reporter structure containing luciferase under the control of a steroid hormone-responsive promoter Yes.

The culture medium used for the culturing of the cells used in the assay was 100 U penicillin / 0.1 μg / ml streptomycin (PAA, Cat: P11-010), 4 mM mM L-glutamine (PAA, Cat: M11-004) and Fetal bovine serum (BIO Witthaker, Cat: DE14-801F) was provided DMEM EARLE'S MEM (PAA, Cat .: E15-025).

For the measurement of anti-mineral corticosteroid efficacy, 1 nM of aldosterone (A-6628 from SIGMA, Lot 22H4033) was added to the cells to achieve nearly maximum stimulation of the reporter gene. Inhibition of the effect indicated the mineral adrenal cortex-antagonist action of the substance (Table 2; corresponding value of drospirenone (A) for comparison).

6. Measurement of androgen / antiandrogen action by cross activation test:

The androgen / antiandrogen action of the test substance was measured as in the cross activation test described above.

The following modifications were used: In this case a reporter cell line (PC3 cells) expressing a reporter structure containing luciferase under the control of the androgen receptor and steroid hormone-responsive promoter was used.

The culture medium used for the culturing of the cells used in the assay was 100 U penicillin / 0.1 μg / ml streptomycin (PAA, Cat: P11-010), 4 mM mM L-glutamine (PAA, Cat: M11-004) and RPMI media without phenol red (PAA, # E15-49) provided with fetal bovine serum (Bio Whitaker, Cat: DE14-801F).

For the measurement of anti-androgen efficacy, almost maximal stimulation of the reporter gene was achieved by adding 0.05 nM of R1881 to the cells. Inhibition of the effect indicated the androgen-antagonistic action of the substance (Table 2; corresponding value of drospirenone (A) for comparison).

If not described herein for the preparation of the starting compound, it is known to those skilled in the art or may be prepared analogously to known compounds or methods described herein. Isomer mixtures can be separated into individual compounds by common methods such as crystallization, chromatography or salt formation. The salt is added to the solution of the compound having the general formula (I) in the usual manner by the addition of an equivalent or excess base or acid, optionally in solution, to separate the precipitate as necessary or by treating the solution in a general manner. Are manufactured.

Compounds having the general formula (I) are prepared by the methods shown in Scheme 1, starting with compounds having the general formula (1a) (Scheme 2) or 1b (Scheme 3), wherein R ⁴ , R ^6a , R ^6b , R ⁷ , R ¹⁵ , R ¹⁸ and Z have the meanings mentioned above, provided that R ⁶ , R ⁷ together in the compound having the general formula 8b together form oxygen or methylene, wherein

R ^16a , R ^16b together form a methylene in the compound having general formulas 32a and 40a,

In compounds having the general formulas 32b and 40b together, they form 1,2-ethanediyl,

In compounds having the general formulas 32c and 40c, independently of one another, hydrogen, C ₁ -C ₁₀ -alkyl,

U is an oxygen atom, two alkoxy groups OR ¹⁹ , or a C ₂ -C ₁₀ -alkylene-α, ω-dioxy group, which can be linear or branched, and R ¹⁹ represents a C ₁ -C ₂₀ -alkyl moiety ,

R ²⁰ is a C ₁ -C ₂₀ -alkyl moiety,

X is NR ^21a R ^21b group or alkoxy group OR ²² ,

R ^21a , R ^21b independently of one another form hydrogen, C ₁ -C ₁₀ -alkyl, or together form a C ₄ -C ₁₀ -α, ω-alkylene group, which can be linear or branched,

R ²² is a C ₁ -C ₂₀ -alkyl moiety.

Those skilled in the art will appreciate that the techniques for synthetic modifications always assume that other functional groups present on the steroid structure are suitably protected as needed.

The introduction of 6,7-double bonds involving the formation of compounds having the general formulas 5, 8a, 10 or 12 may result in the removal of hydrogen bromide following the bromination of 3,5-dienol ether 4, 7, 9 or 11, respectively. (See J. Fried, JA Edwards, Organic Reactions , for example). in Steroid Chemistry , from Nostrand Reinhold Company 1972, p. 265-374).

Dienol ether bromination of compounds 4, 7, 9 or 11 can be carried out as for example in the specification of Steroids 1, 233 (1963). Removal of hydrogen bromide with the formation of compounds having the general formula 5, 8a, 10 or 12 is carried out in combination with a basic reactant such as LiBr or Li ₂ CO _{3 in an} aprotic solvent such as dimethylformamide. By heating the compound to a temperature of 50-120 ° C. or alternatively by heating the 6-bromo compound in a solvent such as collidine or lutidine.

Introduction of the substituent R ⁴ can be effected, for example, starting with a compound having one of the general formulas 3, 5, 6, 8a, 8b or 10, epoxidation of 4,5-double bonds with hydrogen peroxide in alkaline conditions, and suitable The epoxide produced in the solvent can be carried out by reaction with an acid having the general formula HR ⁴ , wherein R ⁴ can be a halogen atom, preferably chlorine or bromine. Compounds in which R ⁴ represents bromine are, for example, 2,2-difluoro-2- (fluorosulfonyl) methyl acetate in the presence of copper (I) in dimethylformamide, and compounds in which R ⁴ represents fluorine Can be reacted with. Alternatively, starting with a compound having one of the general formulas (3), (5), (6), (8a), (8b) or (10), halogens may be directly reacted by reaction with sulfuryl chloride or brominated sulfuryl in the presence of a suitable base such as pyridine. By this introduction, R ⁴ can represent chlorine or bromine.

Compounds 5 or 12 are known methods using, for example, dimethylsulfonium methylate (e.g. DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US- A 4,291,029; see the J. Am . Chem . Soc . 84, 867 (1962), by methenylation of 6,7-double bonds to a mixture of α- and β-isomers (e.g. Which can be separated into individual isomers) to compound 8b or 13 (R ⁶ , R ⁷ together form a methylene group).

Compounds of type 8b or 13 may be obtained as described in the Examples, or using reactants similar to those described there, analogously to the present specification.

The synthesis of spirocyclic compound 10 (R ^6a , R ^6b together form 1,2-ethanediyl) begins at compound 3 or 6, which first starts with 3-amino-3,5-diene derivative 7 (X = NR ^21a R ^21b ). By reaction with formalin in alcohol solution, 6-hydroxymethylene derivative 8a (R ⁶ = hydroxymethylene) is obtained. The hydroxyl group is converted to a leaving group such as mesylate, tosylate or even benzoate and then reacted with trimethylsulfonium iodide using a base such as alkali hydroxide, alkali alcoholate in a suitable solvent such as dimethyl sulfoxide. Compound 10 can be prepared by this.

To introduce the 6-methylene group, compound 8a (R ⁶ = hydroxymethylene) can be dehydrated using hydrochloric acid in dioxane / water, for example. By converting the hydroxyl groups once again into leaving groups such as mesylate, tosylate or even benzoate, compound 10 (R ^6a , R ^6b together form methylene) can be obtained (DE-A 34 02 329, EP-A 0 150 157, US-A 4,584,288; see J. Med . Chem . 34, 2464 (1991).

Another possibility for the preparation of 6-methylene compound 10 is 4 (5) unsaturated 3-ketones, for example compound 8a (R), in the presence of sodium acetate having phosphoryl chloride or phosphorus pentachloride in a suitable solvent such as chloroform, for example. ⁶ = hydrogen) is a direct reaction of formaldehyde with acetal (see, eg, K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).

The 6-methylene compound may be used to prepare a compound of Formula 10 wherein R ^6a is methyl and R ^6b and R ⁷ together form an additional bond.

To this end, for example, Tetrahedron 21, 1619 (1965). It is possible to use a method as described here, wherein a 5% palladium / charcoal catalyst pretreated with hydrogen or by heating with a small amount of cyclohexene is used. Isomerization of the double bond is achieved by heating the 6-methylene compound in ethanol. Isomerization may also be carried out using an unpretreated catalyst when a small amount of cyclohexene is added to the reaction mixture. The formation of consumption hydrogenation products can be prevented by adding excess sodium acetate.

Alternatively, compound 9 (X = OR ²² ) can be used as precursor. Direct preparation of 6-methyl-4,6-dien-3-one derivatives has been described (K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb . Ann . 712 (1983) ] Reference).

Under appropriate conditions, the 6-methylene compounds by hydrogenation: A from ^{R 6b (10 R 6a, R} 6b together form a methylene) may be prepared compounds 10 representing the α- methyl functional group. Best results (selective hydrogenation of exo-methylene functionality) are achieved by transfer-hydrogenation ( J. Chem . Soc. 3578 (1954)). When the 6-methylene derivative 10 is heated in a suitable solvent such as ethanol in the presence of a hydride donor such as cyclohexene, the 6α-methyl derivative is obtained in very good yield. Consumption rates of 6β-methyl compounds can be isomerized under acidic conditions ( Tetrahedron 1619 (1965)].

Selective preparation of 6β-methyl compounds is also possible. To this end, 4-en-3-one, such as compound 8a, can be reacted with ethylene glycol, trimethyl orthoformate, for example in dichloromethane in the presence of a catalytic amount of acid, for example p-toluenesulfonic acid, and a corresponding 3 Reacts with ketal During this ketalization there is an isomerization of the double bond to position C ⁵ . Selective epoxidation of such 5-double bonds is achieved by using organic per-acids, such as m-chloroperbenzoic acid, in a suitable solvent, for example dichloromethane. As an alternative, the epoxidation may be carried out using hydrogen peroxide, for example in the presence of hexachloroacetone or 3-nitrotrifluoroacetophenone. The 5,6α-epoxide formed can then be opened on-axis using a suitable halogenated alkylmagnesium or alkyllithium compound. In this way, a 5α-hydroxy-6β-alkyl compound is obtained. By cleaving the 3-keto protecting group by treatment in weak acid conditions (acetic acid or 4N hydrochloric acid at 0 ° C.), a 5α-hydroxy functional group can be obtained. Basic removal of 5α-hydroxy functional groups, for example using dilute aqueous sodium hydroxide solution, yields a 3-keto-4-ene compound having a 6-alkyl group at the β position. Alternatively, cleavage of the ketal under more severe conditions (using aqueous hydrochloric acid or another strong acid) yields the corresponding 6α-alkyl compound.

Introduction of a 7-alkyl, 7-alkenyl or 7-alkynyl group to form a compound having the general formula (6) adds 1,6- addition of the corresponding organometallic compound to the precursor having the general formula (5) under copper salt action Is performed by. Divalent metals such as magnesium and zinc are preferred; Chlorine, bromine and iodine are preferred as counterions. Suitable copper salts are monovalent or divalent copper compounds, for example copper chloride, copper bromide or copper acetate. The reaction takes place in an inert solvent such as tetrahydrofuran, diethyl ether or dichloromethane.

Obtained compounds 3, 5, 6, 8a, 8b, 10, 11 or 12, in which Z represents an oxygen atom, are hydroxylamine hydrochloride, alkyloxyamine hydrochloride in the presence of tertiary amine at temperatures of -20 ° C to + 40 ° C. Reaction with chloride or sulfonyl hydrazine can be converted to its corresponding E / Z-aligned oxime or sulfonyl hydrazone (General Formula I in which Z represents NOR ¹ , NNHSO ₂ R ¹ ). Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazicyclo [4.3.0] non-5-ene (DBN) and 1,5- As diazabicyclo [5.4.0] undec-5-ene (DBU), pyridine is preferred. Similar methods are described for example in the preparation of the corresponding 3-oxyimino derivatives of drospirenone in WO-A 98/24801.

For the preparation of the final product having the general formula (I) in which Z represents two hydrogen atoms, for example according to the instructions set forth in DE-A 28 05 490, for example, the general formulas 3, 5, 6, 8a, 8b 3-oxo groups can be removed by reductive cleavage of thioketals of 3-keto compounds on suitable precursors of compounds having one of 10, 11 or 12.

The formation of spirolactone for the compound having one of the general formulas 3 or 8b is carried out by oxidation starting from the corresponding 17-hydroxypropenyl compound 2 or 13. Oxidation processes that may be mentioned include, for example, Jones oxidation, such as oxidation with potassium permanganate in an aqueous system of tert-butanol and sodium dihydrogen phosphate, optionally in the presence of a chlorine trap, such as 2 Oxidation with sodium chloride in aqueous tert-butanol in the presence of -methyl-2-butene or oxidation with manganese dioxide.

<Scheme 1>

<Scheme 1 (continued)>

Compounds having the general formula 1a are prepared by the method shown in Scheme 2, wherein

R ¹⁵ and R ¹⁸ have the aforementioned meaning,

R ^16a , R ^16b together form a methylene at 32a,

In 32b together form 1,2-ethanediyl,

At 32c independently of one another is hydrogen, C ₁ -C ₁₀ -alkyl,

R ²⁰ is C ₁ -C ₂₀ -alkyl.

Compounds 30-1a of Scheme 2 each have a double bond between C ⁵ and C ⁶ or between C ⁵ and C ¹⁰ , and another double bond between C ² and C ³ or between C ³ and C ⁴ .

<Scheme 2>

Compounds having the general formula (Ib) are prepared by the method shown in Scheme 3, wherein

R ¹⁵ and R ¹⁸ have the aforementioned meaning,

R ^16a , R ^16b together form a methylene at 40a,

At 40b together form 1,2-ethanediyl,

At 40c independently of one another is hydrogen, C ₁ -C ₁₀ -alkyl,

U is an oxygen atom, two alkoxy groups OR ¹⁹ , a C ₂ -C ₁₀ -alkylene-α, ω-dioxy group, which can be linear or branched, and R ¹⁹ represents a C ₁ -C ₂₀ -alkyl moiety.

Compounds 38-1b of Scheme 3 each have a double bond between C ⁴ and C ⁵ or between C ⁵ and C ⁶ or between C ⁵ and C ¹⁰ .

<Scheme 3>

[Example]

The following examples are provided for further explanation of the invention, but the invention is not limited to the embodiments shown.

Example 1 (Dienon Formation from Dienol Ether):

17β-hydroxy-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-lactone

A solution of 4.12 g of compound prepared according to Example 1a in 448 mg of sodium acetate, 4.5 ml of water, and a total of 1.73 g of dibromohydantoin in small portions at -10 ° C. in 44.8 ml of N-methylpyrrolidone Was added. After 30 minutes, 1.68 g of lithium bromide and 1.48 g of lithium carbonate were added and the mixture was heated to a bath temperature of 100 ° C. for 1 hour. The mixture was poured into a mixture of ice and sodium chloride solution and the precipitated product was filtered off by suction. 3.83 g of the title compound was isolated as crude product, which was further reacted immediately or further purified by recrystallization.

Example 1a (Dienol Ether Formation):

17β-hydroxy-3-methoxy-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

695 mg of pyridinium-p-toluenesulfonate was added to a solution of 6.02 g of the compound prepared according to Example 1b in 68.7 ml of 2,2-dimethoxypropane and heated at reflux for 2 hours. The mixture was poured into saturated sodium hydrogen carbonate solution and extracted several times with ethyl acetate, then the combined organic extracts were washed with saturated sodium chloride solution and the product dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by recrystallization. 4.12 g of the title compound was isolated.

Example 1b (17-spirolactoneization with manganese dioxide):

17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

2.03 g of manganese dioxide was added to a solution of 269 mg of the compound prepared according to Example 1c in 21 ml of dichloromethane and the mixture was stirred at 23 ° C. for approximately 5 hours. Next, 211 mg of the title compound was isolated as a crystalline solid by filtration over Celite and concentration by evaporation and chromatography.

Example 1c (3-ketal cleavage):

17α (Z)-(3'-hydroxypropen-1'-yl) -17β-hydroxyestra-4-en-3-one

1.51 ml of 4 N hydrochloric acid was added to a solution of 367 mg of the compound prepared according to Example 1d in 30 ml of acetone and the mixture was stirred at 23 ° C. for 30 minutes. It was then poured into saturated sodium hydrogen carbonate solution, extracted several times with ethyl acetate, and then the combined organic extracts were washed with saturated sodium chloride solution and the product dried over sodium sulfate. The residue obtained after filtration and removal of solvent was purified by chromatography. 269 mg of the title compound was isolated.

Example 1d (Lindlar hydrogenation):

17α (Z)-(3'-hydroxypropen-1'-yl) -3,3-dimethoxy-17β-hydroxyestra-5 (10) -ene

5.35 ml of pyridine and 560 mg of palladium on barium sulfate were added to a solution of 3.94 g of the compound prepared according to Example 1e in 90 ml of tetrahydrofuran and the mixture was hydrogenated under a hydrogen atmosphere. The mixture was filtered over celite and concentrated by evaporation and chromatography to isolate 3.04 g of the title compound.

Example 1e (with hydroxypropine):

17α- (3'-hydroxypropyn-1'-yl) -3,3-dimethoxy-17β-hydroxyestra-5 (10) -ene

A 2.5 molar solution of butyllithium in 1.13 l of hexane was added to a solution of 92.7 ml of 2-propyn-1-ol in 1.4 l of tetrahydrofuran at -60 ° C. After 30 minutes, a solution of 100 g of 3,3-dimethoxy-estra-5 (10) -en-17-one in 0.8 l of tetrahydrofuran was added dropwise and the mixture was heated to 23 ° C., followed by an additional 16 hours. Was stirred. The mixture was then poured into water, extracted several times with ethyl acetate, and then the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by crystallization. 72.9 g of the title compound was isolated.

Example 2 (1,6-addition):

17β-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β- Methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

A 3 molar solution of methyl magnesium chloride in 193 μl tetrahydrofuran was added dropwise to a suspension of 4.6 mg of copper (I) chloride in 0.7 ml of tetrahydrofuran cooled to −30 ° C. and stirred for an additional 10 minutes. The solution was cooled to -25 ° C and added dropwise to 75 mg of the compound prepared according to Example 1 in 2 ml of tetrahydrofuran. After 1 minute, it was poured into 1 N hydrochloric acid, extracted several times with ethyl acetate, and then the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent was purified by chromatography. 23.4 mg of the title compound A was isolated with the mixture still contaminated, which contained some title compound B.

Example 3:

17β-hydroxy-7α-ethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β- Ethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 2, 100 mg of the compound prepared according to Example 1 was reacted with ethyl magnesium chloride and after treatment and purification, 19 mg of the title compound A was isolated with the still contaminated mixture, which was Some title compound B was contained.

Example 4:

17β-hydroxy-7α-vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β- Vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 2, 700 mg of the compound prepared according to Example 1 was reacted using vinylmagnesium chloride, and after treatment and purification, 46 mg of the title compound A was isolated with the still contaminated mixture, which was Some title compound B was contained.

Example 5:

16,16- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

358 mg of the title compound were isolated by reacting 400 mg of the compound prepared according to Example 5a similarly to Example 1b, followed by treatment and purification.

Example 5a:

16,16- (1,2-ethanediyl) -17α (Z)-(3'-hydroxypropen-1'-yl) -17β-hydroxyestra-4-en-3-one

1.64 g of the title compound were isolated by reacting 2.83 g of the compound prepared according to Example 5b, similarly to Example 1c, followed by treatment and purification.

Example 5b:

3,3-dimethoxy-16,16- (1,2-ethanediyl) -17α (Z)-(3'-hydroxypropen-1'-yl) -17β-hydroxyestra-5 (10) -yen

2.98 g of the compound prepared according to Example 5c were reacted and treated similarly to Example 1d, whereby 2.84 g of the title compound was isolated and further reacted without purification.

Example 5c:

3,3-dimethoxy-16,16- (1,2-ethanediyl) -17α (Z)-(3'-hydroxypropyn-1'-yl) -17β-hydroxyestra-5 (10) -yen

By treating and purifying 100 mg of the compound prepared according to Example 5d similarly to Example 1e, 116 mg of the title compound was isolated and further reacted without purification.

Example 5d (16,16-cyclopropane from 16-methylene):

3,3-dimethoxy-16,16- (1,2-ethanediyl) -estra-5 (10) -en-17-one

A 60% suspension of sodium hydride in 1.05 g of white oil was added to a solution of 5.61 g of sulfoxium iodide in 100 ml of dimethyl sulfoxide in small portions at 23 ° C. It was stirred for an additional 2 hours, then a solution of 2.1 g of the compound prepared according to Example 5e in 40 ml of dimethylsulfoxide was added dropwise and the solution was left to react for an additional 16 hours. The mixture was poured into water, extracted several times with ethyl acetate, and then the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. 2.52 g of the title compound, still containing a residual amount of white oil, was isolated and further reacted without further purification.

Example 5e (16,16-methylene from silyleneol ether):

3,3-dimethoxy-16-methylene-estra-5 (10) -ene-17-one

6.1 g of 3,3-dimethoxy-17-trimethylsilyloxy-estra-5 (10) 16-diene in 10 ml of N, N, N ', N'-tetramethyldiaminomethane in 30 ml of tetrahydrofuran Solution was added, and after cooling to 3 ° C., 10 ml of acetic anhydride was added. The mixture was heated to 23 ° C. and left to react for 2 days. It was then poured into saturated sodium hydrogen carbonate solution, extracted several times with ethyl acetate, and then the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. By purification of the product by silica-gel chromatography; 1.6 g of the title compound was isolated.

Example 6:

17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

9.3 g of the title compound were isolated by reacting 10 g of the compound prepared according to Example 6a in a similar manner to Example 1b, followed by treatment and purification.

Example 6a:

17α (Z)-(3'-hydroxypropen-1'-yl) -18-methyl-17β-hydroxyestra-4-en-3-one

6.35 g of the compound prepared according to Example 6b were reacted analogously to Example 1c and then treated and purified to isolate 3.02 g of the title compound.

Example 6b:

17α (Z)-(3'-hydroxypropen-1'-yl) -3-methoxy-18-methyl-17β-hydroxyestra-2,5 (10) -diene

By treating and reacting 7.86 g of the compound prepared according to Example 6c, similarly to Example 1d, 6.35 g of the title compound was isolated and further reacted without purification.

Example 6c:

17α (Z)-(3'-hydroxypropyn-1'-yl) -3-methoxy-18-methyl-17β-hydroxyestra-2,5 (10) -diene

Isolate 7.86 g of the title compound by reacting 5.0 g of 3-methoxy-18-methyl-17β-hydroxyestra-2,5 (10) -diene-17-one in a similar manner to Example 1e and then treating And further reacted without purification.

Example 7:

17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-lactone

5.04 g of the title compound was isolated by reacting 9.0 g of the compound prepared according to Example 7a, similarly to Example 1, followed by treatment and purification.

Example 7a:

17β-hydroxy-3-methoxy-18-methyl-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

By treating and reacting 10.0 g of the compound prepared according to Example 1b, similarly to Example 1a, 10.9 g of the title compound was isolated and further reacted without purification.

Example 8:

17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy- 7β, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 2, 200 mg of the compound prepared according to Example 7 was reacted using methyl magnesium chloride and after treatment and purification, 115 mg of the title compound A was isolated with the still contaminated mixture, which was Some title compound B was contained.

Example 9:

17β-hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydro Roxy-7β-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 2, 200 mg of the compound prepared according to Example 7 was reacted with ethyl magnesium chloride, and after treatment and purification, 91 mg of the title compound A was isolated with the still contaminated mixture, which was Some title compound B was contained.

Example 10:

17β-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydro Roxy-7β-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 2, 200 mg of the compound prepared according to Example 7 was reacted using vinylmagnesium chloride, and after treatment and purification, 74 mg of the title compound A was isolated with the still contaminated mixture, which was Some title compound B was contained.

Example 11:

17β-hydroxy-7α-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β- Hydroxy-7β-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 2, 200 mg of the compound prepared according to Example 7 was reacted using cyclobromized magnesium bromide, and after treatment and purification, 38 mg of the title compound A was isolated with the still contaminated mixture, It contained some title compound B.

Example 12:

17β-hydroxy-7α-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β -Cyclopropyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 2, 300 mg of the compound prepared according to Example 1 was reacted using cyclochloromagnesium chloride, and after treatment and purification, 89 mg of the title compound A was isolated with the still contaminated mixture, It contained some title compound B.

Example 13 (4-chlorination):

4-Chloro-17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

20 μl of Sulfuryl Chloride was added to a solution of 50 mg of the compound prepared according to Example 6 in 0.5 ml of pyridine at 3 ° C. and stirred at 3 ° C. for an additional 1.5 h. The solution was poured into saturated sodium hydrogen carbonate solution, extracted several times with ethyl acetate, and then the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent was purified by chromatography. 14 mg of the title compound was isolated.

Example 14:

4-Chloro-17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

Similar to Example 13, 100 mg of the compound prepared according to Example 1b was reacted, and after treatment and purification, 77.8 mg of the title compound was isolated.

Example 15 (Introduction of 6-hydroxymethyl):

17β-hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

427 μl of 37% aqueous formaldehyde solution was added to a solution of 427 mg of the compound prepared according to Example 15a in 4 ml of toluene and 9 ml of ethanol mixture and stirred at 23 ° C. for 6 hours. After the solution was concentrated by evaporation, the residue was purified by chromatography. 23.4 mg of the title compound was isolated.

Example 15a (Dieneamine Formation):

17β-hydroxy-3-pyrrolidinyl-18-methyl-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

280 μl of pyrrolidine was added to a solution of 500 mg of the compound prepared according to Example 1b in 5 ml of methanol and heated at reflux for 2 hours. The mixture was cooled and the precipitate was filtered off by suction and washed again with slightly cold methanol to give 434 mg of the title compound which was reacted further without further purification.

Example 16 (6-spirocyclopropane):

6,6- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ -Lactone

235 mg of trimethylsulfonium iodide was dissolved in 1.7 ml of dimethylsulfoxide and 43 mg of 60% sodium hydride dispersion was added and the mixture was stirred at 23 ° C. for 2 hours. Next, a solution of 140 mg of the compound prepared according to Example 16a in ... (?) Ml dimethylsulfoxide was added dropwise and the mixture was stirred at 23 ° C. for an additional 2 hours. The mixture was poured into water, extracted several times with ethyl acetate, and then the combined organic extracts were washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent was purified by chromatography. 38.2 mg of the title compound was isolated.

Example 16a (6-Tosyloxymethyl Formation):

17β-hydroxy-6β- (p-tolylsulfonyloxymethyl) -18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ- Lactone

1.5 ml of triethylamine and 514 mg of p-toluenesulfonic acid were added to a solution of 400 mg of the compound prepared according to Example 15 in 15 ml of dichloromethane and stirred at 23 ° C. for 15 hours. The mixture was poured into saturated sodium carbonate solution and extracted several times with ethyl acetate, then the combined organic extracts were washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent was purified by chromatography. 145 mg of the title compound was isolated.

Example 17:

17β-hydroxy-6β-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

Similar to Example 15, 156 mg of the title compound were isolated by reacting, then treating and purifying 517 mg of the compound prepared according to Example 17a.

Example 17a:

17β-hydroxy-3-pyrrolidinyl-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

Similar to Example 15a, 524 mg of the title compound was isolated by reacting, then treating and purifying 840 mg of the compound prepared according to Example 1b.

Example 18:

6,6- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

Similar to Example 16, 26 mg of the title compound was isolated by reacting 80 mg of the compound prepared according to Example 18a, followed by treatment and purification.

Example 18a:

17β-hydroxy-6β- (p-tolylsulfonyloxymethyl) -19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

Similar to Example 16a, 80 mg of the title compound was isolated by reacting 540 mg of the compound prepared according to Example 17, followed by treatment and purification.

Example 19 (Corey cyclopropane):

17β-hydroxy-18-methyl-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β -Hydroxy-18-methyl-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 16, 188 mg of the title compound A and 430 mg of the title compound B were isolated by reacting 1.5 g of the compound prepared according to Example 7, followed by treatment and purification.

Example 20:

17β-hydroxy-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy- 6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

Similar to Example 16, 66 mg of the title compound A and 112 mg of the title compound B were isolated by reacting 1.28 g of the compound prepared according to Example 1, followed by treatment and purification.

Example 21:

The lumen of the rat uterus is filled with an inert reservoir system consisting of a biodegradable polymer or a synthetic silicone polymer, consisting of an active ingredient-containing core in an appropriate polymer-active ingredient mix ratio, which is suitable for intrauterine implantation and ensures a desired daily release rate. Introduced. The female animals were previously removed from the ovaries and pretreated with estradiol for 3 days. In order to investigate the local and systemic progesterone effects of the released active ingredient based on various parameters in different tissues, implants of different lengths (5-20 mm) and limited diameters (1.1-2 mm) were 4-14 days old. Rats were kept in utero. The following parameters were measured: 1) local progesterone effect on the uterus, based on the weight of the uterus, histologically detectable epithelial height and the expression of the progestogen-regulating marker gene (eg IGFBP-1); 2) systemic progesterone effects on the mammary gland based on expression of progestogen-regulating marker genes (such as RankL); 3) Systemic progesterone effects on the pituitary gland, based on LH concentration (reduction of estrogen-induced elevation of LH concentration).

The compounds of the present invention showed significant progesterone effects in the uterus comparable to the corresponding treatment with levonorgestrel-containing reservoir systems such as Mirena®.

Claims (29)

17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivatives having the formula (I) and solvates, hydrates, stereoisomers and salts thereof.
<Formula I>

(here
Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'and NNHSO ₂ R', wherein R 'is hydrogen, C ₁ -C ₁₀ -alkyl, aryl or C ₇ -C ₂₀ -aralkyl,
R ⁴ is selected from the group containing hydrogen and halogen,
Also
R ^6a , R ^6b are each independently of each other selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl and C ₂ -C ₁₀ -alkynyl, or together methylene or To form 1,2-ethanediyl,
R ⁷ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₁₀ -alkenyl and C ₂ -C ₁₀ -alkynyl, or
or
R ^6a , R ⁷ together form an oxygen atom or methylene, or are omitted with the formation of a double bond between C ⁶ and C ⁷ ,
R ^6b is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl and C ₂ -C ₁₀ -alkynyl,
Also
R ¹⁵ is hydrogen,
R ^16a , R ^16b are each independently selected from each other from the group comprising hydrogen and C ₁ -C ₁₀ -alkyl, or together form methylene or 1,2-ethanediyl,
or
R ¹⁵ and R ^16a are omitted together to form an oxygen atom or to form a double bond between C ¹⁵ and C ¹⁶ ,
R ^16b is hydrogen or C ₁ -C ₁₀ -alkyl,
R ¹⁸ is hydrogen or C ₁ -C ₃ -alkyl,
Except for 17α- (2-carboxyvinyl) -17β-hydroxy-19-nor-androst-4-en-3-one γ-lactone. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to claim 1, wherein Z is selected from the group comprising oxygen, NOR 'and NNHSO ₂ R'. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to claim 1, wherein Z represents oxygen. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 3, wherein R ⁴ is hydrogen or chlorine. The 17-hydroxy-19-nor-21- according to any one of claims 1 to 4, wherein R ^6a , R ^6b together form 1,2-ethanediyl, or each is hydrogen. Carboxylic acid-steroid γ-lactone derivatives. The 17-hydroxy-19-nor-21-carboxylic acid- according to any one of claims 1 to 5, wherein R ⁷ is selected from the group comprising hydrogen, methyl, ethyl and vinyl. Steroid γ-lactone derivatives. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 4, wherein R ^6a and R ⁷ together form methylene. The 17-hydroxy-19-nor-21-car according to any one of claims 1 to 4, wherein R ^6a and R ⁷ are omitted with the formation of a double bond between C ⁶ and C ^7. Acid-steroid γ-lactone derivatives. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 8, wherein R ¹⁵ is hydrogen. The 17-hydroxy compound according to any one of claims 1 to 8, wherein R ¹⁵ , R ^16a is omitted while a double bond is formed between C ¹⁵ and C ¹⁶ , or together forms an oxygen atom. -19-nor-21-carboxylic acid-steroid γ-lactone derivatives. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 9, wherein R ^16a is hydrogen and R ^16b is methyl. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 9, wherein R ^16a and R ^16b are hydrogen. The 17-hydroxy-19-nor-21-carboxylic acid according to claim 1, wherein R ^16a and R ^16b together form methylene or 1,2-ethanediyl. -Steroid γ-lactone derivatives. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 13, wherein R ¹⁸ is hydrogen or methyl. The 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 14, selected from the group comprising:
17β-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ lactone
17β-hydroxy-7β-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7α-ethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7β-ethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7α-vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7β-vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7α-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7β-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-6-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-6α-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-6β-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
6,6- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-lactone
16,16- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-ethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-ethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-vinyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-vinyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-cyclochloro-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-6-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-6α-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ- Lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-6β-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ- Lactone
(E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -diene- 21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ- Lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ- Lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-19-nor-17α-pregna-4,6,20 (Z) -triene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -16,16- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -diene- 21-carboxylic acid γ-lactone
17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7β, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7β-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7β-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7α-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-7β-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-18-methyl-6-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-6α-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
6,6- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ -Lactone
17β-hydroxy-18-methyl-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-18-methyl-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-lactone
16,16- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ -Lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ- Lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ- Lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-cyclochloro-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxyl Acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxyl Acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -triene-21-carboxylic acid γ -Lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-6-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-6α-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-car Acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-car Acid γ-lactone
(E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z ) -Diene-21-carboxylic acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-car Acid γ-lactone
(E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-car Acid γ-lactone
(E / Z) -3- (hydroxyimino) -17γ-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -triene-21-carboxylic acid γ -Lactone
(E / Z) -3- (hydroxyimino) -16,16- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z ) -Diene-21-carboxylic acid γ-lactone
4-Chloro-17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone
4-Chloro-17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone. The 17-hydroxy-19-nor-21-carboxylic acid- according to any one of claims 1 to 15, for oral contraception and for the treatment of premenopausal, premenopausal and postmenopausal complaints. Steroid γ-lactone derivatives. 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivatives according to any one of claims 1 to 16 for oral contraception and premenopausal, premenopausal and postmenopausal complaints Use for the manufacture of a therapeutic pharmaceutical product. Use according to claim 17, characterized in that the medicinal product has a progesterone action, an anti-mineral corticosteroid action, and a neutral action on some androgens. A medicament containing at least one 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 16 and at least one suitable pharmaceutically harmless carrier material. product. The pharmaceutical product according to claim 19, further comprising one or more estrogens. The pharmaceutical product according to claim 20, wherein the estrogen is ethynylestradiol. The pharmaceutical product according to claim 20, wherein the estrogen is estradiol valerate. The pharmaceutical product according to claim 20, wherein the estrogen is a natural estrogen. The pharmaceutical product according to claim 23, wherein the natural estrogen is estradiol. The pharmaceutical product according to claim 23, wherein the natural estrogen is a conjugated estrogen. Use of the 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 14 for the manufacture of a medicinal product for intrauterine use. The use of claim 26 for the manufacture of an intrauterine system (IUS). Containing at least one 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivative according to any one of claims 1 to 14 and at least one suitable pharmaceutically harmless additive, Medicine characterized in that designed for my use. The pharmaceutical product according to claim 28, which is an intrauterine system.